Derivatives of aminoalkanoic acids

ABSTRACT

(3,4,5-TRIALKOXY BENZOYL) AMINO ALKANOIC ACIDS AND THEIR PHARMACEUTICALLY-ACCEPTABLE SALTS FOR PROPHYLAXIS AND TREATMENT OF CARDIAC DISORDERS.

United States Patent Garzia 1 Sept. 19, 1972 [54] DERIVATIVES OF AMINOALKANOIC ACIDS [72] Inventor: Aldo Garzia,Lodi,ltaly [73] Assignee: lnstituto Chemioterapico Italiano S.P.A., Milan, Italy 22 Filed: June 26,1970

211 Appl. No.: 50,329

[52] US. Cl. .260/519, 424/319, 260/404 [51] Int. Cl ..C07c 103/22 [58] Field of Search ..260/519, 404

[56] References Cited UNITED STATES PATENTS 3,489,793 I/ 1970 Bertelli ..260/519 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. Arnold Thaxton Attorney-John W. Behringer, Eugene L. Bernard,

Martin J. Brown, James N. Dresser, W. Brown Morton, Jr., John T. Roberts, Malcolm L. Sutherland and Morton, Bernard, Brown, Roberts & Sutherland s7 ABSTRACT 7 Claims, No Drawings DERIVATIVES OF AMINOALKANOIC ACIDS BACKGROUND OF THE INVENTION This invention relates to a method of prophylaxis and treatment of cardiac disorders. In a particular aspect, it relates to a method of treating ischemic cardiopathy prior to or following a cardiac infarction, disorders of rhythm, and disorders of stimulus transmission by the administration of an aminoalkanoic acid derivative.

The prevention and treatment of cardiac disorders, such as ischemia, thrombosis, cardiac infarction and disorders of rhythm and stimulus transmission, is-a serious problem. Many studies have been conducted in an effort to ascertain the underlying causes and to develop a suitable method of preventing or treating these serious problems, particularly cardiac insufficiency and cardiac infarction. The pharmacological methods which have been proposed for preventing cardiac infarction include lowering of blood cholesterol levels, relaxation of the arteries and administration of anticoagulants. Ventricular fibrillation is a highly dangerous condition which is treated by electric shock administered to the heart muscle, and other rhythm and transmission disorders respond to installation of the pacemaker" device.

While the use of these methods has greatly improved the prognosis of cardiac patients, the problem of cardiac disorders generally still remains a severe one and in particular the problems caused by infarction are still grave.

SUMMARY OF THE INVENTION It is an object of this invention to provide a method of prophylaxis and treatment of cardiac disorders.

It is another object of this invention to provide novel pharmaceutical compositions suitable for the prophylaxis and treatment of the cardiac disorders.

Another object of this invention is to provide a method of prophylaxis and prevention of ischemic cardiopathy, cardiac infarction and disorders of rhythm and stimulus transmission by the administration of the derivatives of aminoalkanoic acids.

Other objects of this invention will be readily apparent to those skilled in the art from the disclosure herein.

It has been discovered that administration of compounds corresponding to the following formula where x is an integer of 3-8, and each of R R and R is methyl, ethyl or propyl, provided that at least one of R, R and R is other than methyl, or their pharmaceutically acceptable salts, is effective in the prophylaxis and treatment of cardiac disorders such as cardiac ischemia and infarction, disorders of rhythm and disortiers of stimulus transmission. The compound is administered at a dosage of 2-8 grams per day per average 60-70 kg. individual. When administration is by intravenous or intraperitoneal injection, soluble, pharrnaceutically acceptable salts of the compounds of this invention are preferred.

DETAlLED DISCUSSION The compounds of the present invention are prepared by reacting the appropriate 3,4,5-trialkoxy benzoyl chloride with the corresponding amino-alkanoic acid at a temperature of about -5 to +5 C. According to the process of this invention, the free amino acid is slurried in about an equal weight of water and is neutralized with sodium hydroxide solution (about 30 percent by weight). Excess sodium hydroxide is added to promote the reaction. The mixture is chilled to within -5 C to +5 C, and the tri-substituted benzoyl chloride is gradually added with agitation, maintaining the temperature at below 5 C. The mole ratio of amino acid to the acid chloride is generally about 1-1 .5 l The resulting solution is stirred for from 2 to 4 days and when the reaction is complete can be treated with char to decolorize it. It is then neutralized with dilute HCl or H to about a pH of 3 or a Congo red indicator endpoint. The resulting precipitate is separated, e.g., by filtration or centrifugation, washed with water, dried, then recrystallized from water or ethanol, separated by filtration, centrifugation or decantation and dried.

According to the method of the present invention, compounds corresponding to the formula given hereinbefore are administered for the treatment of cardiac ischemia, either prior to or following a cardiac infarction, disorders of the rhythm whether related to the infarction or not, and disorders of stimulus transmission. Administration of these compounds is an effective prophylaxis in cases of an impending cardiac infarction and aneffective treatment after infarction has occurred. According to one embodiment of the present invention, the method is employed in veterinary.

medicine, principally in the treatment of household pets, especially dogs, where cardiac problems are frequently encountered.

Cardiac infarction frequently occurs without prior symptoms or before the patient has sought treatment for the relief of symptoms. However physicians are frequently able to detect symptoms of an approaching crisis and the administration of the compounds of this invention can be started promptly to obtain prophylactic effects.

The products of the present invention are of a low order of toxicity and no side effects are observed in clinical trials. Pharmacological studies indicate that the principal effect of the compounds of the invention is on the heart. The only observed effect on the circulatory system is an increase in the static blood pressure with no significant change in mean arterial pressure.

The dosage in which the compounds of the present invention can be given can vary widely within ratherbroad limits. Good results have been obtained with as little as 25mg/kg/day and as much as 500 mg/kg/day. In human clinical cases, all of the disorders cited above generally respond to a dosage of 2-8g per day per person, preferably about 6g per day. This dosage is intended for an average 60-70 kg individual equivalent to a dosage generally within the range of about 25-200 mg/kg/day. A dosage in the range of about 40-100 mg/kg/day is preferred. The treatment can consist of a single daily dose, or the above dosages can be given fractionally at periodic intervals. A single daily dose is generally preferred for a treatment of cardiac infarction and associated disorders but for prophylaxis, smaller periodic doses, e.g., a 500 mg dose, six times daily, is preferred.

Administration of the compounds of this invention can be oral, subcutaneous, intravenous or intraperitoneal. When the compounds of the present invention are by subcutaneous, intraperitoneal or intravenous injection, they are administered as their water-soluble neutral salts. Any soluble, pharmaceutically acceptable salt is suitable and the sodium and potassium salts are preferred. The sodium salt is particularly preferred. For oral administration the compounds are preferably administered as the free acids but they can also be pharmaceutically acceptable salts, e.g., as the ammonium, sodium, potassium, magnesium or calcium salt. According to one suitable method, the free acids can be administered mixed with a molar equivalent of sodium or potassium bicarbonate. In the examples, the compounds were administered intraperitoneally as the sodium salt because of its ease of handling as an aqueous solution, but the weights given are for the free acid.'When administered orally, the compounds are conveniently administered as tablets containing 500 mg with a suitable binder, many of which are known.

Suitable tablets for human or animal use can conveniently be prepared containing 50500 mg of the compounds of the present invention, either as the free acid or as a pharmaceutically acceptable salt thereof. Tablets containing as little as 50 mg are suitable for oral administration, especially for infants and small children, and in veterinary medicine, for small animals. Tablets containing less than 50 mg can be prepared, and in special cases may beuseful, but generally a dose smaller than 50 mg is too small. to be practical because in the average patient the number of tablets required per day would be excessively high for convenience. Tablets containing more than 500 mg can also be prepared, but large tablets are difficult for most patients to swallow.

EXAMPLE 1 Seven grams of e aminocaproic acid were suspended in 7 cc of water and neutralized with 10 percent sodium hydroxide. Then 4.l grams of 97 percent NaOH dissolved in 20 cc of water were added. To this was added slowly at -l0 C, 11.5 grams of the chloride of 3,5-diethoxy-4-methoxybenzoic acid. This was stirred overnight and then acidified with dilute hydrochloric acid. The precipitate was filtered and washed with water and petroleum ether. The product was crystallized from water giving crystals melting at l05-l06 C and assaying 100.59 percent. The product was 3,5 diethoxy-4-methoxybenzoyl-e-aminocaproic acid.

EXAMPLE 2 T0 14 milliliters of water were added 14 grams of 95 percent e-aminocaproic acid and the mixture was neutralized with a percent sodium hydroxide solution. Then 8.2 grams of sodium hydroxide dissolved in 80 ml. of water were added. Then 22 grams of the chloride of 3,4,5-triethoxybenzoic acid were added slowly at 940 C and the mixture was stirred 3-4 hours at room temperature. The solution was treated with charcoal, filtered and acidified with dilute hydrochloric acid to pH 3. This gave 30 grams of product melting at l l5-l 16 C. Recrystallization from 750 ml. of water plus 250 ml. of ethanol gave a product melting at l20-l22 C and assaying 102.43 percent. The product was 3,4,5-triethoxybenzoyl-e-aminocaproic acid.

EXAMPLE 3 33 4/10 grams (0.2 mole) of e-aminocaproic acid hydrochloride dissolved in 20 milliliters of water was neutralized with 50 percent sodium hydroxide. Then a solution of 12 grams of sodium hydroxide dissolved in 120 ml. of water was added. The solution was cooled, and 38 grams of the chloride of 3,5-dimethoxy-4-ethoxybenzoic acid was added at 58 C. The mixture was stirred overnight and then acidified with dilute hydrochloric acid. This gave a product which was crystallized from 3,000 mi. of water. The recrystallized product melted at l25-l26C., assayed 98.8 percent; The product was 4-ethoxy-3,S-dimethoxybenzoyl-eaminocaproic acid.

EXAMPLE 4 11 grams of the hydrochloride of a-aminocaproic acid were dissolved in 15 milliliters of water and neutralized with 10 percent sodium hydroxide solution. Then 5 grams of sodium hydroxide dissolved in 15 milliliters of water was added and the solution was cooled to 5 C. Keeping the temperature between 5 and 8 C., 19 grams of the chloride of 3,4,5-tripropoxybenzoic acid were added while simultaneously adding slowly 200 milliliters of water. The mixture was stirred overnight, then decolorized with charcoal and finally acidified with dilute hydrochloric acid.,Filtration gave a white solid which on crystallization from 800 milliliters of 50-50 ethanol-water gave 21 grams of product; m.p. ll0lll C; assay-99.9 percent. The product was 3,4,5-tripropoxybenzoyl- -aminocaproic acid. The LD of this'product, intraperitoneal, is mg. per kg. and hence is too toxic to be useful therapeutically at this dosage level.

EXAMPLE 5 The effect of the compound prepared according to the procedure of Example 1 on the heart is determined in rats by intravenous injection of l unitper kilogram of vasopressin (Pitressin, marketed by Parke, Davis Co.), an antidiuretic pituitary hormone. As is known, the administration of vasopressin results in variations of the voltage and the morphology, or shape, of the T- wave. It also causes arrhythmia and produces ischemia of the myocardium. it is determined that these electrocardiographic alterations normally produced by the administration of Pitressin are prevented by the administration of the compound of Example 1.

EXAMPLE 6 The effects of the compound of Example 1 is determined on chloroform-epinephrine induced arrhythmias in rats. In the procedure employed, the .rats are anaesthetized with urethane. Chloroform is administered for 1 minute by inhalation and then 100 micrograms/kg of epinephrine hydrochloride is administered intravenously. Electrocardiograms are taken and the extent of the arrhythmia in terms of number of beats per minute is determined. The effect of the compound of Example I is substantially to reduce the extent of the arrhythmia when administered intraperitoneally in the amount of 700 mg/kg.

EXAMPLE 7 A pharmaceutical composition in tablet form is prepared by mixing 500 mg of the compound of Example l with 50 mg of corn starch and 50 mg of sucrose. This mixture is compressed in a tableting machine to make a durable tablet. It is suitable for oral administra- 1 tion to humans or other animals suffering from cardiac disorders. It is particularly suitable for prophylaxis of a suspected impending coronary occlusion resulting in an infarction.

The above examples are representative. For example, the 3,4,5-trialkoxy benzoic acids are well known to the art. See, for example, U.S. Pat. Nos. 3,234,276, 3,364,249 and 3,485,865. e-amino-caproic acid is available in commercial quantity and the commercial grade materials are suitable for preparing the products of this invention. The corresponding aminovaleric, aminobutyric, aminoheptanoic, aminooctanoic and aminononanoic acids are prepared by known methods by the HCl-catalyzed hydrolysis of the corresponding lactams, which are known in the art. The salts thus obtained are then passed through an ion-exchange resin bed to obtain the free amino acid.

The recommended dosage during the first 24 hours following infarction is as follows:

2-4 grams by phleboclysis; 1-2 ampoules (each ampoule containing 2,000 mg of the sodium salt of the compound of Example 1 dissolved in sufficient sterilized distilled water to make 10 cc) dissolved in 400-600 cc of saline solution.

2-4 grams by intravenous administration; 2-4 ampoules divided into 2-4 administrations (each ampoule containing 1,000 mg of the sodium salt of the compound of Example 1 dissolved in sufficient sterilized distilled water to make 10 cc).

2 grams by intramuscular administration; 8 ampoules divided into 4 administrations (each ampoule containing 250 mg of the sodium salt of the compound of Example l and sufficient sterilized distilled water to make 3 cc).

4-6 grams by oral administration; 8-l 2 tablets (each tablet containing 500 mg of the sodium salt of the compound of Example 1 and sufficient excipient to make one tablet).

4-6 grams by oral administration; 8-l2 ampoules (each ampoule containing 1 or 2 grams of the sodium salt of the compound of Example 1 in sufficient sterilized distilled water to make 10 cc).

In the third or fourth day after start of therapy, the dosage can be reduced to half the above amounts. The

0 therapy should not be interrupted before the third week after heart infarction has occurred.

Both in the attack phrase and in the maintenance stage the therapy can be carried out using one or more of the different forms of administration.

I claim:

1. A compound represented by the formula where x is an integer of 3-8, and each '6? R7, R and R is methyl, ethyl or propyl, provided that at least one of R R and R is other than methyl, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where x is 5, R and R are methyl and R is ethyl.

3. The compound of claim 1 where x is 5, R and R are ethyl and R is methyl.

4. The compound of claim 1 where x is 5 and each of R R and R is ethyl.

5. The compound of claim 1 where x is 5, and each of R,, R and R is propyl.

6. The compound of claim 1 wherein the'pharmaceutically acceptable salts are sodium or potassium.

7. A compound represented by the formula "is methyl, ethyl or propyl, provided that at least one of R,, R and R is other than methyl.

UNITED STATES WVEENT OFFECE CETEFECATE 0F CQRECTEQN a Patent No. 3 ,692 8Z7 Dated September 19 1972 Inventor( Garzia It is certified that error vappears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, line 37, ".fitripropoxybenzoylamino...'

should read -tripropoxybenzoyl- -aminoc:aproic Signed and sealed this-3rd day of July 1975.

SEAL Attest:

EDWARD M.FLETCHER ,JR. Rene Tegtmeye'r Attesting Officer ting Commissioner of Patents Q P434050 uscoMM-oc 60376-P69 U. 5 GOVERNMENT PRINTING OFFICE: 1969 0-366-334, 

2. The compound of claim 1 where x is 5, R1 and R3 are methyl and R2 is ethyl.
 3. The compound of claim 1 where x is 5, R1 and R3 are ethyl and R2 is methyl.
 4. The compound of claim 1 where x is 5 and each of R1, R2 and R3 is ethyl.
 5. The compound of claim 1 where x is 5, and each of R1, R2 and R3 is propyl.
 6. The compound of claim 1 wherein the pharmaceutically acceptable salts are sodium or potassium.
 7. A compound represented by the formula where x is an integer of 3-8, and each of R1, R2, and R3 is methyl, ethyl or propyl, provided that at least one of R1, R2 and R3 is other than methyl. 